Process for the preparation of pyrazinoylguanidines



United States Patent 3,449,341 PROCESS FOR THE PREPARATION OF PYRAZINOYLGUANIDINES Peter I. Pollak, Scotch Plains, and Roger J. Tull, Me-

tuchen, N.J., assignors to Merck & Co., Inc., Rahway, N .J., a corporation of New Jersey No Drawing. Filed Apr. 30, 1968, Ser. No. 725,504 Int. Cl. C07d 51/76; A61]: 27/00 U.S. Cl. 260--250 4 Claims ABSTRACT OF THE DISCLOSURE A process is described for the preparation of pyrazinoylguanidines which comprises thetreatment of the corresponding pyrazinirnidoylguanidines with acid. The products have utility as diuretic and/or saluretic agents with potassium sparing properties.

action of a 3,5-diamino-6-halopyrazinimidoylguanidine;

I, with a mineral acid to give the desired 3,5-diamino-6- halopyrazinoylguanidine, II. The reaction is represented by the following equation:

The reaction comprises dissolving Compound -I in a solution of a mineral acid such as hydrochloric, hydrobromic, sulfuric and the like, of acid strength from 1 to about 12 normal, preferably containing at least one equivalent of acid per mole of Compound II. The acid solution can be aqueous or aqueous alcohols such as methanol, ethanol, propanol or isopropanol. After standing for from 1 to about 10 hours at room temperature of [from 1 to about 3 hours at temperatures up to the reflux temperature of the solvent, the crystalline acid addition salt of 3,5- diamino-6-halopyrazinoylguanidine crystallizes from the solution.

While the novel method of this invention can be employed to produce substantially any 3,5-diamino-6-halopyrazinoylguanidine product the reaction is particularly useful in the preparation of products of Formula II wherem R represents (a) hydrogen, (b) lower alkyl of from 1 to about carbon atoms such as methyl, ethyl, propyl, butyl and pentyl, either straight or branched chain and either un- 3,449,341 Patented June 10, 1969 substituted or substituted with lower cycloalkyl, having from 1 to 6 carbon atoms such as cyclopropyl, cyclopentyl and cyclohexyl, and

(0) lower alkenyl;

R represents (a) hydrogen, and '(b) lower alkyl of from 1 to about 3 carbon atoms such as methyl, ethyl and propyl;

R represents (a) hydrogen,

(b) lower alkyl of from 1 to about 3 carbon atoms such as methyl, ethyl or propyl, either unsubstituted or substituted with such as hydroxyl, or mononuclear aryl, especially phenyl;

R represents (a) hydrogen, or (b) lower alkyl from 1 to about 3 carbon atoms such as methyl, ethyl, and propyl;

and X represents (a) hydrogen ,or (b) halo such as chloro, bromo and iodo.

While the following examples illustrate the novel process of this invention, it is to be understood that the examples are not to be considered as limiting the invention to the particular products prepared or to the particular embodiments of the invention falling within the scope of the reaction conditions and products described herein above.

EXAMPLE 1.3,5-DIAMINO-6-Cd-ILOROPYRA- ZINOYLGUANIDINE Step A:Preparation of 3,5-diamino-6-chloropyrazinimidoylguanidine Sodium (460 mg., 0.02 mole) is dissolved in anhydrous isopropyl alcohol (50 ml.). The solution is cooled, and dried pulverized quanidine hydrochloride (1.9 g., 0.02 mole) is added an the mixture is stirred mechanically and refluxed for 30 minutes. After cooling and removing the precipitated sodium chloride by filtration, the filtrate is treated with 3,S-diamino-6-chloropyrazinonitrile (0.01 mole). The mixture'is stirred mechanically for 2 hours at room temperature and the solvent is then removed by reduced pressure distillation at room temperature. The resulting solid is suspended in a little water, filtered, washed with water and dried, yielding 1.25 g. of 3,5-diamino-6 chloropyrazinimido-ylguanidine. The compound is purified by suspending in water, dissolving by adding dilute hydrochloric acid, filtering, precipitating with dilute sodium hydroxide, collecting by filtration, washing with water and drying.

Step B.-'Preparation of 3,5-diamino-6-chloropyrazinoylguanidine 3,5-diamino-6-chloropyrazinimidoylguanidine (1 mole) is dissolved in 1 liter of 2 N hydrochloric acid. After standing 2 hours at ambient temperature, the crystalline product of 3,5-diamino-6-chloropyrazinoylguanidine hydorchloride separates out. It is collected on a filter, washed with cold water and dried. It has M.P. 293.5 C. (decomp.).

Other 3-amino-5-NR R 6-halopyrazinoylguanidine compounds prepared by the process of this invention are described in the following table of examples. The products are prepared rfollowing substantially the same process described in Example 1, Step B, except that the 3,5- diamino-6-chloropyrazinimidoylgu'anidine employed in Example 1, Step B, is replaced by the 3-amin0-5NR R -6- halopyrazinimidoylguani'dine having the variable R R R and R as defined in the following table. All other 3 4 reagents and reaction conditions for the preparation of (d) lower(cycloalkyl-alkyl); the product are as described in Example 1, Step B, al- R is a member selected from the group consisting of though the modifications hereinbeifore described can be in- (a) hydrogen, and corporated to ultimately give the desired (3-amino-5- (b) lower alkyl; NR R -6-halo pyrazinoyl)- 3-R -3-R -guanidines also de- 5 R is a member selected from the group consisting of fined in the following table. (a) hydrogen,

N N N NH: e N NH: R R x CNHCN X NHON/ N u u N 1| 1| NH R 0 NH R Ex. R R R R X M.1 (0.) 2 CH3' CH3'' H H Cl 216-217 H H HO(CH2)2 H 01 22s. -229. 5 4 l-CzHr- H 0113 0H; 01 238.5240

5 -0H=- H H H 01 220-221 6 CH2=CHGHicH3- H H 01 207-208 7 C2H5- CzH 0H3- CHa- 01 212-214 B i-03H1- H HO)CH2)z- H Cl 185-186 1101. =Ho1-%(H=0.

What is claimed is: (b) lower alkyl, 1. A process for the preparation of a compound of (c) hydroxy-lower alkyl, and structural formula (d) phenyl-lower alkyl;

R R is a member selected from the group consisting of N (a) hydrogen, and a (b) lower alkyl; and 2 X is halo.

x f fi" 2. The process as claimed in claim 1 wherein the 0 NH R mineral acid is hydrochloric acid. which comprises the treatment of a compound of struct- The process as clalmed m clalm 1 wherem R R2, l fo l R and R are hydrogen.

R1 4. The process as claimed in claim 3 wherein X is N chloro.

N NH: 3 1 i 40 References Cited X C--NHC-N H H UNITED STATES PATENTS NH NH 3,361,748 1/1968 Chagoe et a1. 260-250 with a mineral acid wherein R is a member selected from the group consisting of NICHQLAS S. RIZZO, Primary Examiner.

(a) hydrogen, ([3) 1 alkyl, US Cl. X.R. (c) lower alkenyl, and 260999 

